Plasmodium parasites cause the disease malaria, which kills close to one million people per year. The disease is formidable, due to the spread of drug-resistant parasite strains, insecticide-resistant mosquito vectors and the inherent difficultis in the implementation and maintenance of effective control programs. Today, emerging resistance to artemisinin combination therapy, which is the standard drug treatment for uncomplicated malaria, poses a significant threat to malaria control. Understanding the genetic basis of antimalarial drug resistance is key and will inform development of new interventions. Experimental crosses between malaria parasite strains are the most powerful way to determine the genetic determinants of phenotypes, and importantly, have been successfully used to determine the genetic basis of P. falciparum drug resistance in the past. To date however, only three P. falciparum experimental crosses have been carried out due to the enormous practical and financial hurdles associated with the process, which cannot be performed in humans, and thus used splenectomized chimpanzees. The genetic analysis of recombinant progeny from a well-conceived cross can be extremely powerful for pinpointing the genetic loci determining a phenotypic trait and has important advantages over population genetic studies. Given the recent decision by the NIH to cease the use of chimpanzees in biomedical research, experimental crosses will no longer be available, effectively rendering future forward genetic studies impossible. However, we have recently shown that a mouse harboring human hepatocytes (the FRG KO huHep mouse) infused with human red blood cells can support P. falciparum sporozoite infection, complete liver stage development as well as the transition to asexual blood stage replication. We hypothesize that the FRG KO huHep mouse can be utilized successfully for routine and robust P. falciparum experimental crosses, thereby replacing the previously essential chimpanzee host. We have data to show that we are able to perform experimental genetic crosses utilizing this model and the crosses generated independent recombinant progeny that we will use for analysis of recombination as well as genotypes and associated phenotypes. Furthermore, we have also carried out an experimental cross with a recent field isolate resistant to artemisinin, allowing us to study the basis of artemisinin resistance. Combined with rapidly improving technologies, such as parasite genetic manipulation, high throughput phenotyping and Systems Genetics, a powerful model for malaria genetic research is now within reach.